ABSTRACT

It is proposed that major depressive disorder is inappropriate 'sickness behavior' generated by abnormalities in cytokines, and that antidepressants exert their specifically beneficial effects through analgesic action on the core dysphoric emotion of malaise. This is termed the malaise theory of depression, and leads to a wide range of testable predictions.

The malaise theory of depression: Major depressive disorder is sickness behavior and antidepressants are analgesic

Introduction - deficiencies in current understanding

The diagnostic syndrome of major depressive disorder (MDD) is traditionally classified as an 'affective disorder' - that is, as an illness primarily of mood. But the nature of the depressive mood state remains elusive. Many MDD patients deny that they feel sad or miserable, and the diagnostic schemas (such as DSM-IV and ICD-10) specify a variety of 'characteristic' mood states such as hopelessness, 'anhedonia' (reduced or absent capacity to experience pleasure), anxiety, distress and irritability. This variety of dissimilar moods in MDD seems excessively imprecise to constitute a primarily 'affective' diagnostic category.

It has proved difficult to conceptualize how 'sadness' could constitute an illness, and even harder to imagine how ingesting a simple chemical could specifically alleviate sadness and restore normal 'euthymic' mood. The conceptual inadequacy transmits itself to patients who cannot understand the rationale for drug (or ECT) treatment, except to suppose that these are euphoriant 'happy pills'. But antidepressants are not euphoriants in the manner of amphetamine or cocaine, nor do they intoxicate, nor are antidepressants considered to be addictive or dependence-inducing and recreational abuse is very rare (Healy, 1996). What antidepressants do not do is therefore well established - yet their positive psychological action remains obscure. To make matters worse, antidepressants are commonly supposed to have a delay of two to six weeks before the onset of therapeutic action. If true, this would make antidepressants unique in pharmacology, since the slowest of other agents onset of action within at most a few days (eg. hormones that affect DNA transcription, such as cortisol or thyroxine).

The problem here is theoretical: since the psychological nature of depression is unclear (Charlton, 1995), the way in which antidepressants act upon depression is unclear, and the current rationale for drug treatment of MDD is also unclear (Charlton, 1998). I propose a unifying theoretical framework for understanding depression and antidepressant action which has the potential to elucidate all these problems. As well as its primary virtue of making-sense in scientific and clinical terms, the malaise theory of depression also has the important advantage of being comprehensible and rational in 'lay' terms.

MDD is sickness behavior

Since major depressive disorder (MDD) is a recurrent pattern or signs and symptoms, it is reasonable to seek an adaptive function for this pattern which might explain why it occurs in a predictable form throughout populations and cross-culturally. Having established a plausible evolutionary function for the MDD syndrome, we can ask how the MDD syndrome is generated and ask what are the factors which mediate it. Finally, any clinically useful theory should be able to explain the ways in which pharmacological and other interventions have beneficial effects in patients suffering from MDD.

The evolutionary function of the behavioral pattern of major depressive disorder can be elucidated by a comparison with other animals. MDD turns out to be near-identical with the adaptive state termed sickness behavior (SB) in animals. Sickness behavior was first described by a veterinarian as a physiological and psychological adaptation to acute infective and inflammatory illness in many mammalian species (Hart, 1988). The characteristic pattern of sickness behavior comprises pyrexia, fatigue, somnolence, psychomotor retardation, anhedonia (lack of ability to experience pleasures such as eating and sex) and impaired cognitive functioning (Kent et al, 1992). In other words the syndrome of SB is almost exactly the same as the standard diagnostic descriptions of MDD (Hickie & Lloyd, 1995; Yirmaya, 1997). The only apparent differences - somnolence and pyrexia - are explicable given that daytime somnolence typically leads to secondary insomnia with nocturnal sleep disruption, and that the presence of pyrexia has not yet been evaluated in MDD.

The evolved function of SB is to act as an energy-conserving, risk-minimizing, immune-enhancing state appropriate for a body mounting a short-term, all-out attack on an invading micro-organism (Hart, 1988; Kent et al, 1992). Major depressive disorder is therefore the behavioral response to a physical illness - it is a syndrome in which low mood is the product of malaise; where malaise describes the symptom of 'feeling ill'. By this account, the feeling of malaise should be regarded as the core emotion of depression (as suggested by Healy, 1990). Therefore major depressive disorder is not primarily an affective disorder: instead the primary pathology in major depressive disorder is somatic, and mood is a secondary and variable response to this disordered physical state.

Cytokines as mediating factors of sickness behavior

If major depressive disorder is sickness behavior - inappropriately-activated or excessively sustained, the next question concerns the 'proximate cause' of this behavioral pattern. Again the evidence appears clear. Mediating factors for the syndrome of MDD seem to involve hyper-activity of the immune system in response to 'non-self' antigenic challenge (for example, inflammation due to infection, carcinoma or 'autoimmune' disease). The chemical factors responsible for mediating sickness behavior appear to be the class of immune active agents known as cytokines (eg. interleukins and interferons (Hart, 1988; Kent et al, 1992; Hickie & Lloyd, 1995; Yirmaya, 1997). Indeed, SB is best considered as an integral and adaptive part of the pyrexial response; it is the behavioral change that assists in the generation and maintenance of raised body temperature produces a diminution of activity appropriate to immune activation.

There is abundant evidence to support the contention that MDD is mediated by cytokines. For instance, administration of cytokines to mammals provides a model for depression: an intravenous infusion of interferon-alpha rapidly produces a syndrome that is psychologically and physically identical with MDD (Smith et al, 1988). And the high incidence of depression and other aversive psychiatric side effects are well-recognized as perhaps the most significant clinical limitation unwanted on the therapeutic use of cytokines (such as interferon and the interleukins) for the treatment of cancer and viral infections (Kent et al, 1992).

The clinical evidence for cytokines being the cause of MDD is also powerful, since there is a substantial literature documenting significant immune activation in depression, with a wide range of abnormalities in cytokines and other acute phase proteins, correlating with the natural history of the illness and response to therapy (Maes et al, 1991; Joyce et al, 1992; Maes et al, 1993; Hickie & Lloyd, 1995; Yirmaya, 1997; Connor & Leonard, 1998). It would be predicted that cytokine abnormalities would be even clearer and more specific if studies were restricted to only those 'depressed' patients who exhibited the syndrome of sickness behavior with prominent symptoms of malaise. Clearly the relationship between specific cytokines, and specific aspects of the MDD syndrome is a potentially fruitful area for future study.

Mood changes secondary to sickness behavior

Although animals demonstrate sickness behavior mediated by cytokines in the same way as humans, only conscious animals such as humans can suffer from the distinctive 'existential' state of depression, with feelings such as nihilism, worthlessness, guilt and suicidal ruminations. The state of malaise which prevails in sickness behavior interacts with memories of the past and anticipations of the future such that a demotivated, exhausted and profoundly dysphoric state of malaise fills and colors past, present, and the anticipations of future mental life.

Prolonged sickness behavior therefore creates a nihilistic mental state where life seems devoid of gratifying possibilities (ie. pessimism) because emotional feedback registers a physiological state that is locked-into sickness behavior, and unresponsive to the usual appetites (ie. a state of anhedonia). Another factor is that the sufferer from SB does not know that they are sick, and often interpret their lack of energy, lack of motivation, and poor concentration as a moral failure - leading to feeling of guilt and unworthiness. Given the nature of this subjective mental landscape, the high rate of suicide in MDD is unsurprising.

To put malaise at the core of the depressive syndrome may seem a radical inversion of the usually accepted causal interpretation, since symptoms of malaise have traditionally been interpreted as secondary to the mood change in MDD. Traditionally (eg. in DSM-IV) it is supposed that depressed people complain of tiredness and aching limbs because they are miserable - whereas the malaise theory suggest that they are miserable because they are tired and have aching limbs. Eventually chronic misery imposes itself on incoming perceptions, these associations are learned, and the depressive cognitive style becomes habitual so it may persist even after resolution of the hyper-immune state that originally caused SB.

To emphasize the physical symptomatology of the depressive is more of a re-emphasis than a novel discovery (Healy, 1990). Kurt Schneider (1959) considered the physical or 'vital' symptoms of depression to be of paramount diagnostic importance and the nearest approach to a 'first rank symptom' of affective disorders. Most comprehensive textbooks of psychiatry or psychopathology describe a range of typical 'depressive' physical symptoms such as exhaustion, washed-out feelings, aching, heaviness, or pain in the head, trunk or limbs (eg. Sims, 1995). Furthermore, modern biological theories of the emotions (especially Damasio, 1994) conceptualize emotions as cognitive representations of somatic states - the link between body and mind has at last been coherently and testably conceptualized. This approach from cognitive neuroscience has already provided preliminary insights into other areas of psychiatry (Charlton & Walston, 1998; Charlton, in the press; Charlton & McClelland, in the press) and its extension to MDD seems amply justified.

The malaise theory of depression suggests that Schnieder's tentative hints were correct, and that a coherent and biologically valid concept of depression can be created with physical symptoms as the unifying primary psychopathology, and affective changes as a secondary, contingent and variable consequence of malaise.

Antidepressants are analgesic

If MDD is SB, and depressed mood is best conceptualized as malaise due to physical illness, what is the action of antidepressants, and how do antidepressants improve depressed mood? In the first place, we must distinguish between specifically antidepressant drugs and those drugs that might in some way be helpful in a depressive illness. I suggest that since malaise is seen as the core symptom of depression, then a specifically antidepressant drug should have as its primary action the alleviation of malaise and the other 'vital' physical symptoms of MDD such as fatigue, heaviness, aches and pains. Other drugs than specific antidepressants may, of course, be valuable in the treatment of other aspects of the MDD syndrome, by alleviating symptoms and signs such as insomnia, hallucinations, anxiety or weight loss; but the core activity of antidepressants should refer to the core symptoms - i.e. the primary, 'depressive' mood-creating physical symptoms associated with malaise.

The cytokine-induced fatigue, demotivation, aches and pains that occur during acute infectious diseases such as influenza, are symptoms usually treated by analgesia (eg. aspirin or acetaminophen). I suggest that, in this sense, antidepressants are analgesics - because any drug that alleviates subjectively dysphoric states can legitimately be considered analgesic. My assertion is therefore that antidepressants are drugs whose specifically anti-depressant action is the symptomatic treatment of an aversive physical state to make patients feel better - very much as aspirin can make patients with 'flu' feel better. When patients feel less 'sick', their mood will - usually - start to improve.

There is considerable evidence to support the idea that tricyclic antidepressants are analgesics when tested in both human and animal models (Lee & Spencer, 1977; Portenoy & Kanner, 1996; Xia et al 1996). Furthermore, tricyclics are increasingly used in the management of chronic pain, neurogenic pain, migraine, chronic fatigue, cancer pain, and arthritis (Panerai, 1991; Portenoy & Kanner, 1996; McDaniel et al, 1995; Holland et al, 1998) .I suggest that analgesia is not just a fortuitous side-effect of tricyclics, but the primary effect of any specifically 'antidepressant' drug. The analgesic effects of non-tricyclic classes of antidepressant are less clearcut - but there is some evidence that fluoxetine and phenelzine are also analgesic (Holland et al, 1998; Portenoy & Kanner, 1996).

So, antidepressants do not 'make people happy' but instead, when effective, they remove a significant obstacle to happiness. It is easier to be happy without malaise, and antidepressants get their effect from being anti-malaise analgesics. Conceived in this fashion, the effect of antidepressants on mood is no more remarkable than the fact that it is easier to be happy without a chronic headache than with one; this is the answer to the apparent paradox that a simple chemical can apparently treat human misery.

Some implications of the malaise theory
The apparently delayed effect of tricyclic antidepressants on mood presumably arises because the response of mood to analgesia is less specific, slower and more unpredictable than the primary analgesic action (which, as for other analgesics, probably has a rapid onset within hours of reaching an effective dose) A rapid onset of antidepressant action is, in fact, compatible with already existing evidence, given the deficiencies of most studies (Muller & Moller, 1998). Of course, following prolonged malaise, the accumulation of dysphoric memories might leave habitual cognitive style (ie. mood) largely unaffected, despite relief of the current state of malaise. But by concentrating on measuring mood, researchers on the mode of action of antidepressants have, in effect, studied the wrong outcome variable - almost as if one were to measure the effect of aspirin on happiness instead of on headache.

The malaise theory would predict that a specifically active antidepressant should have a significant effect on the core symptoms of malaise within hours of reaching an effective dose, although mood may take some weeks to lift (Healy, 1990). If confirmed, a reliable prediction of effective antidepressant activity depending up an analgesic action which has rapid onset could have immediate and important therapeutic implications. Currently it takes four to six weeks to conclude that an antidepressant is not going to work before trying another drug; and many of these apparently 'late responses' may be natural remissions. If therapeutic trials could be shortened to a week at a therapeutic dose, or even shorter, it would mean that the 'trial and error' process of discovering an effective antidepressant would be much more rapid.

There are, of course, many other implications of the malaise theory of depression than can be dealt with in the scope of the current paper, although all have some preliminary support in the current literature. Briefly these include: that depression would more effectively be treated symptomatically rather than syndromally; that since tricyclic antidepressants are analgesic, then other conventional analgesics (aspirin, acetaminophen, opiates) may be antidepressant; that tricyclics may have a therapeutic role in common malaise states such as colds and flu; and that MDD patients should be pyrexial in the early stages of their illness. Some of these predictions would be simple to test.

Conclusion

The most striking aspect of the malaise theory of depression is that it is about the body and not the brain. It suggests that the minimal or core state of depression is a 'normal' brain's response to an abnormal body state; and that the action of antidepressants involves an analgesic effect that may be wholly peripheral. Of course, this just defines the minimum state of MDD; and depressive symptoms may coexist with brain involvement in an inflammatory or other pathological process - this is probably a factor in those patients with 'psychotic symptoms' such as psychomotor retardation, hallucinations or delusions.

It is also important to emphasize that MDD is a maladaptive manifestation of sickness behavior. When SB occurs as a short-term response to acute infection it is (usually) adaptive; but when SB is activated outside of the circumstance for which it evolved, it should be considered dysfunctional. For example, in an acute infectious illness the state of demotivation is valuable in conserving energy for an all-out fight against infection. But when sickness behavior is sustained or inappropriately evoked, a long-term state of demotivation may be profoundly damaging to personality, social or occupational life.

In summary, it has been argued that major depressive disorder is inappropriate sickness behavior, that the syndrome of MDD is generated by abnormalities in cytokines, and that antidepressants exert their specifically beneficial effects through analgesic action on the core dysphoric emotion of malaise. This is termed the malaise theory of depression, and leads to a wide range of testable predictions.

Footnotes
Acknowledgements: Thanks are principally due to Dr David Healy for ideas, insights and criticism across his extraordinary range. Dr Antonio R Damasio's fundamental concept of the 'somatic marker mechanism' was also of critical importance. Dr Gavin Spickett furnished important immunological reassurance. A comment from patient AK provided the vital clue.

Lee R, Spencer PSJ. (1977). Antidepressants and pain: a review of the pharmacological data supporting the use of certain tricyclics in chronic pain. Journal of International Medical Research 5, supplement 1: 146-156.

It is usually assumed in general medical practice that when a sick person develops a depressed mood this is an understandable consequence of factors such as restricted physical activity and pain. An alternative perspective has been argued which suggests that classical ‘depressive’ symptoms are often caused by activation of the immune system (especially cytokines such as interleukins, interferons and tumor necrosis factor etc) which produces the state of malaise [1,2].

Malaise comprises fatigue, heaviness, dull, pains, aching of limbs and trunk, lack of energy and altered sleep patterns. These depressive symptoms seem to be the human equivalent of “sickness behaviour” which is a stereotypical response of mammals suffering from infectious or inflammatory diseases [3]. In other words, malaise is a behavioural pattern that is adaptive in acute infectious illnesses, ensuring that the animal will rest and conserve energy to mount an all-out immune attack on infective pathogens - depressive illness occurs when this syndrome is maladaptively severe or sustained [2].

In a preliminary study, the relationship between poor health and depressive symptoms was investigated using the SF-36 and Beck Depression Inventory. The SF-36 is a well-validated 36-item health-status questionnaire, which provides an overall measure of general health and specific dimensions of health which include vitality, physical functioning, functional performance, pain and mental health [4]. The Beck Depression Inventory (BDI) is a widely used self-administered scale to measure the severity of depressive symptoms using a twenty-six item questionnaire [5].

Thirty six subjects (17 male, 19 female) were studied in a convenience sample. There was a significant negative correlation between the SF-36 overall score (general health) and the score on the BDI, (correlation coefficient r = -0.611, p<0.001) confirming that depressive symptoms tends to occur with poor health. There were significant (p<0.05) correlations between the BDI score and SF-36 subscales for mental health (r = -0.707), physical health (r = -0.62), and vitality (r = 0.662). However, there was no statistically significant correlation between the BDI score and subscales measuring physical functioning, limitations on activity due to physical problems, or bodily pain. This suggests that lowered mood cannot simply be explained as due to physical restriction and pain.

A further study compared depressive symptoms in two groups of subjects matched for severity of sickness: one group having systemic illnesses, and the other group having physical injuries. Nineteen physically injured subjects (11 males, 8 females), and 17 systemically subjects (6 males, 11 females) were studied from a convenience sample. Subjects with physical injuries comprised 8 ligament, cartilage and muscle injuries; 6 with back and joint pain, and 5 with fractures and dislocations. Systemically ill subjects comprised 12 with symptoms of colds, flu, glandular fever and sore throats; 8 with headaches; 6 with pyrexia and sweats; 3 with aches and pains; two with fatigue and 4 others (some subjects had more than one symptom).

The SF-36 overall health scores were not significantly different in the systemically ill and injured groups (Kruskal-Wallis test p > 0.1). However scores on the BDI were clearly distinct between the two groups. Among physically injured subjects 84% scored 0-4 ‘no or minimal depression’; 11% scored 5-13 ‘mild depression; and one outlier scored 15 ‘moderate depression’. By contrast, among systemically ill subjects only 12% scored 0-4 %; while 88% scored 5-13 ‘mild depression’. The difference between the two groups was highly statistically significant (p<0.001 Kruskal-Wallis test).

These studies suggest that depressive symptoms are much commoner in systemic illness than physical injury of similar severity. This is consistent with the Malaise theory [2] that depressive symptoms are more likely to be caused by immune activation than by physical restriction and pain. If the results are confirmed, one implication may be that depressive symptoms in systemically ill patients could be alleviated by treatment of the symptoms of malaise.